Approximately one million cases of stone disease are diagnosed in the United States every year and hyperoxaluria is considered to be a major risk factor. Our goal is to reduce the burden of oxalate excretion by the kidneys before the onset of renal failure caused by the oxalate-induced insults of hyperoxaluria, oxalate crystal deposition in tissue, and the formation of calcium oxalate stones. The studies proposed here represent a continuation of investigations that were initiated to specifically develop an oral supplementation therapy, using the substrate-specific, gut bacteria Oxalobacter or its products, for the control of hyperoxaluric conditions. Thus far, our studies have revealed the important physiological role of intestinal secretory/excretory pathways in shifting the balance of oxalate excretion between the renal and enteric routes of elimination. We have shown that a cell lysate preparation from Oxalobacter stimulated the active transport systems involved in colonic oxalate excretion in addition to enzymically degrading oxalate in solution. Subsequently, we showed an impressive reduction in urinary oxalate excretion in vivo, in rats with oxalate- induced renal failure by administering encapsulated Oxalobacter lysate compared to placebo. The present objective is to produce a therapeutic supplement which will maximally exploit the combination of these two actions in order to control hyperoxaluric conditions. PROPOSED COMMERCIAL APPLICATIONS: The development of an effective supplementation therapy for the control of hyperoxaluric conditions is timely. Currently, there are 1 million patients with kidney stone disease and there are patients with other oxalate-associated diseases, including primary hyperoxaluria which invariably results in death at an early age due to oxalate-induced kidney failure. The potential for the clinical application of a novel treatment strategy to reduce urinary oxalate excretion is broad-based and highly significant.